Phellinus pini Polysaccharides Regulate Gut Microbiota-Host Metabolism to Attenuate Influenza-Driven Lung Injury

Phellinus pini is a large fungus with significant medicinal value. Building on the previously discovered inhibitory activity of Phellinus pini polysaccharides (PPP) against influenza viruses, this study established an influenza A mouse model through the intranasal instillation of an H1N1/PR8 virus solution. Using a combination of metabolomics and gut microbiota analysis techniques, the study further elucidated a novel mechanism by which PPP regulates influenza-induced lung damage via the "gut-lung axis". Results showed PPP reversed lung lesions, reduced the lung index and viral load in lung tissue, and exerted anti-inflammatory effects by downregulating inflammatory cytokine expression, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Additionally, 49 potential biomarkers were identified in fecal samples collected from mice infected with influenza A. After low-dose PPP administration, 16 of these biomarkers returned to normal levels. Further pathway analysis revealed that PPP primarily exerts its antiviral effects by influencing pyrimidine metabolism, steroid hormone biosynthesis, tyrosine metabolism. Gut microbiota analysis revealed that PPP improves the gut microbiota environment by significantly increasing the abundance of beneficial bacteria, such as Alistipes, which is closely related to fructose and mannose metabolism and β-lactam resistance pathways. Spearman's correlation analysis revealed that the 16 PPP-regulated biomarkers were correlated with Alistipes and pharmacological parameters. These integrated results suggest a potential mechanism by which PPP alleviates influenza-driven lung injury through the modulation of the gut microbiota-host metabolism axis. This study provides correlative evidence supporting the involvement of the gut-lung axis in PPP's protective effects, offering theoretical insights for future antiviral research.